Digestive Tract Carcinoma Research Articles

Identification of molecular subtypes and prognostic signature for hepatocellular carcinoma based on genes associated with homologous recombination deficiency

Hepatocellular carcinoma (HCC) is a rapidly developing digestive tract carcinoma. The prognosis of patients and side effects caused by clinical treatment should be better improved. Nonnegative matrix factorization (NMF) clustering was performed using 109 homologous recombination deficiency (HRD)-related of HCC genes from The Cancer Genome Atlas (TCGA) database. Limma was applied to analyze subtype differences. Immune scores and clinical characteristics of different subtypes were compared. An HRD signature were built with least absolute shrinkage operator (LASSO) and multivariate Cox analysis. Performance of the signature system was then assessed by Kaplan–Meier curves and receiver operating characteristic (ROC) curves. We identified two molecular subtypes (C1 and C2), with C2 showing a significantly better prognosis than C1. C1 contained 3623 differentially expressed genes. A 4-gene prognostic signature for HCC was established, and showed a high predicting accuracy in validation sets, entire TCGA data set, HCCDB18 and GSE14520 queues. Moreover, the risk score was validated as an independent prognostic marker for HCC. Our research identified two molecular subtypes of HCC, and proposed a novel scoring system for evaluating the prognosis of HCC in clinical practice.

Impact of Antibiotics and Proton Pump Inhibitors on Efficacy and Tolerance of Anti-PD-1 Immune Checkpoint Inhibitors.

BackgroundThe use of antibiotics (ATB) and proton-pump inhibitors (PPI) alters the composition and diversity of the gut microbiota, which can influence the immune system, consequently interfering with response to anti-PD1 immune checkpoint inhibitors (ICI). We assessed the impact of ATB and/or PPI use on the efficacy and safety of ICI.MethodsTwo hundred twelve patients treated with anti-PD1 ICI for non-small cell lung carcinoma, melanoma, upper airway & digestive tract carcinoma or renal cell carcinoma were retrospectively included. Patients having received ATB within 60 days before ICI initiation were included in the ATB+ group. Patients having received PPI within 30 days before ICI initiation were included in the PPI+ group. Four groups were thus considered: ATB-/PPI-, ATB+/PPI-, ATB-/PPI+, ATB+/PPI+. Response rate was assessed by RECIST v1.1. Overall survival (OS), progression-free survival (PFS) and adverse events, recorded using Common Terminology Criteria for Adverse Events Version 5, were compared using inverse probability of treatment weighting to account for selection bias.ResultsPFS at 6 months was 56.7 %, 95%CI (49.6%; 63.2%) and 47.2 %, 95%CI (39.8%;54.1%) at 12 months. OS was 81.6%, 95%CI (75.6%; 86.2%) at 6 months, and 69.4%, 95%CI (61.9%;75.7%) at 12 months. Compared to ATB-/PPI- group, PFS was lower for the ATB+/PPI- group [Hazard ratio (HR) 1.90, 95%CI (1.41;2.57)] and the ATB-/PPI+ group [HR 1.51, 95%CI (1.11;2.05)], and lowest in the ATB+/PPI+ group [HR 3.65, 95%CI (2.75;4.84)]. For OS, the use of ATB alone or PPI alone or in combination was a risk factor for death, with each increasing HR values by a similar magnitude, and the combination of ATB and PPI did not increase risk further. AEs were observed in 78 cases (36.8%) with no significant impact of ATB or PPI use.ConclusionsThis study reveals that ATB and/or PPI use can alter response to anti-PD1 ICI, and the prognosis of cancer patients. The microbiota mechanisms involved in the response to ICI should be investigated to optimize patient management.

Anti-proliferative activities of coumarins from the Thai medicinal plant Mammea siamensis (Miq.) T. Anders. against human digestive tract carcinoma cell lines

Geranylated coumarins named mammeasins G–J (1–4) were isolated from the methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) originating in Thailand. Their structures were established based on detailed spectroscopic analyses. The isolates, including previously reported coumarin constituents (5–28), exhibited anti-proliferative activities against human carcinoma cell lines HSC-2, HSC-4, MKN-45, and MCF-7. Mammeasin A (7, IC50 = 13.6 μM) and surangin B (15, 15.2 μM), both consisting of the geranyl group, were found to show relatively strong activities against HSC-4 cells and their mechanisms of action were found to involve apoptotic cell death.

Type II Diabetes Mellitus - Associated Risk Factor in the Onset and Evolution of Digestive Tract Carcinoma

Type II Diabetes Mellitus - Associated Risk Factor in the Onset and Evolution of Digestive Tract Carcinoma

Nursing care management of photodynamic therapy in digestive tract carcinomas at a single cancer center

The primary goal of nursing care in cases of endoscopic photodynamic therapy (PDT) for digestive tract carcinoma is to prevent phototoxicity by the intravenous administration of photosensitizers. The adequate protocol and management of patients should be conducted under the instruction of expert physicians. Our experiences of administering porfimer sodium and talaporfin sodium during clinical PDT provide insight regarding the specific management protocol of each photosensitizer during an in-hospital stay. We herein report our nursing protocol based on 15 years of experience. Under adequate management, PDT can be safely performed.

林州上消化道癌早诊早治项目治疗病例分析(2008-2014)

目的：本文报告河南林州市2008-2014年7年间上消化道癌筛查中发现的705例病例的近期治疗结果。方法：按照国家《癌症早诊早治技术方案》对筛查中发现的705例患者分别实施内镜下微创、手术等治疗方法，并进行随访观察生存状况以综合评价。结果：在接受治疗的572病例中，生存542例(94.76%)，死亡25例(4.37%)，死于其他疾病5例(0.87%)；在未接受治疗的133病例中，生存116例(87.22%)，死亡14例(10.53%)，死于其他疾病3例(2.26%)。其存活状况与治疗与否存在着统计学差异。结论：项目的核心不仅贵在早诊，而且要强调早治。资料显示，对于筛查中发现的不同病变，应积极采取相应的规范化治疗。接受治疗与否，对于病人的生存状况有着明显的影响。 Objective: In this paper, to report 705 cases of treatment outcome for Upper Digestive Tract Carcinoma in Linzhou, 2005-2014. Method: in according with the national technical scheme of early cancer diagnosis and treatment programme found in the 705 cases with endoscopic minimally invasive, surgical treatment, and follow-up of survival in a comprehensive evaluation. Results: in the treatment of cases, 542 cases of life (94.76%), 25 cases of death (4.37%), 5 died of other diseases (0.87%), in untreated cases, 116 cases of life (87.22%), 14 cases of death (10.53%), 3 cases died of other diseases (2.26%). Its survival and whether or not there is a significant difference of treatment. Conclusion: the core of the project is not only expensive in early diagnosis, and to emphasize early treatment. Statistics show that found screening for different diseases, should adopt appropriate treatment. Treatment or not, the patient's living conditions had a significant effect.

The Antiproliferative Effect of Chakasaponins I and II, Floratheasaponin A, and Epigallocatechin 3-O-Gallate Isolated from Camellia sinensis on Human Digestive Tract Carcinoma Cell Lines.

Acylated oleanane-type triterpene saponins, namely chakasaponins I (1) and II (2), floratheasaponin A (3), and their analogs, together with catechins—including (–)-epigallocatechin 3-O-gallate (4), flavonoids, and caffeine—have been isolated as characteristic functional constituents from the extracts of “tea flower”, the flower buds of Camellia sinensis (Theaceae), which have common components with that of the leaf part. These isolates exhibited antiproliferative activities against human digestive tract carcinoma HSC-2, HSC-4, MKN-45, and Caco-2 cells. The antiproliferative activities of the saponins (1–3, IC50 = 4.4–14.1, 6.2–18.2, 4.5–17.3, and 19.3–40.6 µM, respectively) were more potent than those of catechins, flavonoids, and caffeine. To characterize the mechanisms of action of principal saponin constituents 1–3, a flow cytometric analysis using annexin-V/7-aminoactinomycin D (7-AAD) double staining in HSC-2 cells was performed. The percentage of apoptotic cells increased in a concentration-dependent manner. DNA fragmentation and caspase-3/7 activation were also detected after 48 h. These results suggested that antiproliferative activities of 1–3 induce apoptotic cell death via activation of caspase-3/7.

Concurrent gastrointestinal stromal tumor and digestive tract carcinoma: A clinical study of 17 patients

Objective To explore the clinical characteristics, diagnosis, treatment and prognosis of the concurrent gastrointestinal stromal tumor and digestive tract carcinoma. Methods Two hundred and eigty nine cases of patients who were diagnosed as gastrointestinal stromal tumors in Jingzhou Central Hospital from July 2010 to June 2015 were concluded in this study. Among them, 170 cases were male and 119 were female. Two Hundred and seventy-two cases (94.1%) were the pure gastrointestinal stromal tumors (single group) and 17 cases (5.9%) combined with digestive tract carcinoma (concurrent group). The clinical data, treatment and prognosis were collected and retrospectively analyzed.Mean were compared by t test and rate compared by Fisher exact probability method. The prognosis of the patiets was analyzed by kaplaln-Meier method and Log-rank method. Results There were no significant differences in gender, age and tumor origin, but there were statistically significant differences in tumor diameter(P<0.001), mitotic index, (P<0.05) and NIH risk classification (P<0.05) between the simple group and the concurrent group. The median follow-up time of the two groups was 30 months (8 to 50 months) in concurrent group and 36 months (12 to 60 months) in single group, and their its prognostic difference was statistically significant (P=0.008). Conclusions There is a low incidence rate of gastrointestinal stromal tumors combined with digestive tract carcinoma and its prognosis is more poorer than the pure gastrointestinal stromal tumors . Radical resection is an effective method for gastrointestinal stromal tumors combined with digestive tract carcinoma. Key words: Gastrointestinal stromal tumors; Gastrointestinal neoplasms; Prognosis

Acylated oleanane-type triterpene saponins from the flowers of Bellis perennis show anti-proliferative activities against human digestive tract carcinoma cell lines.

Seven oleanane-type triterpene saponin bisdesmosides, perennisaponins N-T (1-7), were newly isolated from a methanol extract of daisy, the flowers of Bellis perennis L. (Asteraceae). The structures were determined based on chemical and physicochemical data and confirmed using previously isolated related compounds as references. The isolates, including 13 previously reported perennisaponins A-M (8-20), exhibited anti-proliferative activities against human digestive tract carcinoma HSC-2, HSC-4, and MKN-45 cells. Among them, perennisaponin O (2, IC50=11.2, 14.3, and 6.9μM, respectively) showed relatively strong activities. The mechanism of action of 2 against HSC-2 was found to involve apoptotic cell death.

河南9万例高危人群上消化道癌内镜筛查及早诊早治分析

目的：探讨在河南上消化道癌高发地区开展内镜筛查和早诊早治项目的过程和结果。方法：选择河南上消化道癌高发地区的12个市县，将40~69岁设定为目标人群。除外胃镜检查禁忌症者，按照国家《癌症早诊早治技术方案》，对筛查对象的食管、贲门、胃进行内镜检查并以组织学诊断进行评价。结果：5年来共筛查9万多例，在进入分析的89,495例中，发现各类癌前病变以解剖部位食管、贲门、胃来分，依次为26,199例(29.27%)、23,337例(26.08%)和3248例(5.20%)；共检出上消化道癌病例2095例，检出率2.34%，其中，食管1.38%，贲门0.73%，胃0.33%。早期病例1706例，占81.72%。对3000多例进行了近期随访筛查，对林州5年治疗情况做了简要报告。结论：在上消化道癌高发地区，对40~69岁高危人群开展内镜筛查和实施早诊早治是可行的，对各类癌前病变进行干预并对各类早期阶段癌变开展微创治疗，将会对防治上消化道癌，降低死亡率起到积极地作用。 Objective: To study the process and results of endoscopic screening and early diagnosis and treatment for the cancer of upper digestive tract in high-incidence areas in Henan. Methods: 12 high-incidence cities and counties of upper gastrointestinal carcinoma in Henan province were included in this study. People aged 40-69 were set to the target population. Except contraindications for endoscopy, in accordance with the national technical scheme of early cancer diagnosis and treatment, endoscopic screening and histologic diagnosis for human esophagus, cardia and gaster of the target people were carried out. Results: During the 5-year period, more than 90,000 cases had a total sieve check, and in the 89,495 cases which entered the analysis, various precancerous in anatomy parts esophagus, cardia and gaster were found: 26,199 subjects (29.27%) in esophagus, 23,337 subjects (26.08%) in cardia and 3248 subjects (5.20%) in gaster respectively. A total of 2095 cases were found to have cancers (2.34%), followed by anatomy parts for 1.38%, and 0.73% and 0.33% respectively, among them 1706 cases had early stage with an early diagnosis rate was 81.72%. More than 3000 cases have been followed-up screening in near future, and we made a brief report on the 5-year treatment in Linzhou. Conclusion: The results of this study demonstrate that endoscopic screening and early diagnosis and treatment for the target population aged at 40 - 69 is feasible in high-incidence areas of upper digestive tract carcinoma. We could intervene various types of precancerous lesions and have minimally invasive treatments to cancer developing in the early stages, which have positively effects on the prevention and treatment of upper digestive tract cancer and reducing mortality.

Current status of photodynamic therapy in digestive tract carcinoma in Japan.

Photodynamic therapy (PDT) is an effective local treatment modality as a cancer-specific laser ablation in malignancy of some organs including digestive tracts or bile duct. In Japan, PDT has been applied at the early period after the first clinical induction in 1980’s. Although the useful efficacy was clarified, PDT has not been fully applied because of the phototoxicity of the porfimer sodium. The next generated talaporfin-sodium was used for PDT, in which phototoxicity was reduced and, however, the clinical efficacy for digestive tract malignancy has not yet been clarified. By proceeding the experimental and clinical trials, it is necessary to clarify the evidence of efficacy as a local powerful treatment with the conventional surgery, brachiotherapy and chemotherapy in the future step.

PATHOLOGICAL AND MOLECULAR‐BIOLOGICAL STUDIES ON SEQUENCE FROM REFLUX ESOPHAGITIS TO DEVELOPMENT OF BARRETT's ADENOCARCINOMA

Background: Barrett's adenocarcinoma is considered to develop via a dysplasia‐carcinoma sequence. However, this theory is thought to be incomplete, because the reports supporting it have been led by an investigation using relatively large‐sized neoplasias or biopsy materials. We think that the minute‐sized neoplasias and the propria mucosa adjacent to these lesions must be examined histologically to clarify the histogenesis of digestive tract carcinoma. In the present study, new findings on the histogenesis of Barrett's adenocarcinoma were revealed according to this point described above.Methods: First, Barrett's epithelium (in particular, specialized colmunar epithelium: SCE) was investigated histologically and immunohistochemically. Second, 28 lesions of the super‐minute tubular neoplasia within 1 mm in maximum diameter in Barrett's esophagus (SMBa) were detected by pathological examinations, and loss of heterozygosity of microsatellite markers (TP53, D17S796 and D17S786) in chromosome 17‐related p53 (p53‐LOH) in these SMBa lesions were examined by DNA extraction using microdissection and high resolution fluorescence labeled PCR primers.Results: Histological and immunohistochemical findings showed that the tubules of SCE had a three‐layer structure and typical SCE should be thought to be the large bowel‐type of the intestinal metaplasia (or goblet cell metaplasia) in the cardiac gland mucosa. According to the overexpression of p53 protein labeling index (p53‐LI), the SMBa lesions were divided into two groups. Three lesions with p53‐LI over 90%, which were thought to be intramucosal adenocarcinoma morphologically, showed high frequency of p53‐LOH (loss of heterozygosity) (100%), and 25 lesions with an average p53‐LI of 58%, which were thought to be benign neoplasia morphologically, also showed p53‐LOH (36%).Conclusions: SCE is thought to be the large bowel type of the intestinal metaplasia in the cardiac gland mucosa. Pathological and molecular‐biological findings of SMBa in SCE supports the dysplasia‐carcinoma sequence in the histogenesis of Barrett's cancer and synchronously some SMBa suggests that there is a different route, the so‐called de novo carcinoma theory.

P0567 THE HEDGEHOG TRANSCRIPTION FACTOR GLI3 MEDIATES THE DEVELOPMENT OF INTESTINAL METAPLASIA

Introduction: Helicobacter pylori infects approximately 50% of children worldwide. Chronic infection can initiate a cascade of pathologic changes within the stomach initially with chronic gastritis and atrophy to intestinal metaplasia (IM). Subsequently, in many cases of IM, carcinoma ensues. The pathobiology of IM, however, is not well understood. Recently, Hedgehog signaling molecules have been identified in both human digestive tract tumours as well as in cell lines derived from digestive tract carcinoma. In the embryo Sonic hedgehog (Shh) contributes to the proper specification of the glandular stomach. In its absence, intestinal transformation of the stomach occurs. The aim of this study was to determine the role of the Hedgehog signaling pathway in the development of IM. Methods: We examined mice mutant in Sonic hedgehog, and the downstream transcription factors, Gli2 and Gli3. All three homozygous mutant mice die at or just before birth. Therefore, pregnant mice from wildtype and heterozygous crosses of the three mutant strains were sacrificed at embryonic day 18.5 and their stomachs were dissected out, fixed in paraformaldehyde, dehydrated and embedded in paraffin. Sections were cut and examined for alkaline phosphatase staining (AP). Immunostaining was performed for the intestinal transcription factor, Cdx2, and intestinal mucin, Muc2, two known markers for IM. Results: The stomachs of both Shh and Gli3 but not Gli2 mutant mice demonstrated positive staining for AP in the distal hindstomach. In the Gli3 but not Shh mutant stomachs, both Cdx2 and Muc2 were found expressed in the distal hindstomach. Gli2 mutant stomachs were also negative for Cdx2 and Muc2 expression. Conclusion: The absence of the activated transcription factor Gli3 leads to the development of intestinal metaplasia in the glandular stomach of the mouse. Concurrently, the transcription factor Cdx2 along with Muc2, which Cdx2 is known to regulate, are actively expressed. However, the presence of the cleaved form of Gli3, as in Shh mutant stomach, prevents this activation. We conclude, therefore, that both forms of Gli3 participate in defining the identity of the gastric gland. Further study of the Hedgehog signalling pathway is likely to improve our understanding of the pathogenesis of intestinal metaplasia.

FHIT alterations in human esophageal, gastric and colorectal carcinomas

OBJECTIVE: To assay alterations in the fragile histidine triad (FHIT) gene in human esophageal, gastric and colorectal carcinomas.METHODS: Carcinomatous tissues from 93 patients with digestive tract carcinoma (including 21 esophageal, 43 gastric and 32 colorectal carcinomas) and neighboring non‐carcinomatous tissues were examined in addition to 18 normal tissue samples. From the above tissue samples, RNA was extracted using guanidinium thiocyanate−phenol−chloroform. FHIT gene transcripts were amplified by using nested reverse transcription−polymerase chain reaction (RT‐PCR).RESULTS: Only wild‐type transcripts of the FHIT gene were found in the 18 normal tissue samples. Wild‐type FHIT gene transcripts were found in most carcinoma tissues, with the exception of seven cases (including two esophageal cancers, three gastric carcinomas and two colorectal carcinomas). In addition, abnormal FHIT transcripts were obtained from 33.3% of esophageal carcinomas, 51.7% of gastric carcinomas and 31.3% of colorectal carcinomas. Abnormal FHIT transcripts were obtained from neighboring tissue from 4.8, 20.9 and 9.4% of esophageal, gastric and colorectal carcinomas, respectively. The proportion of abnormal FHIT transcripts in carcinomatous tissues was significantly higher (P &lt; 0.05) than that in neighboring non‐carcinomatous tissues and normal tissues.CONCLUSION: The proportion of abnormal FHIT cDNA in carcinomatous tissue is greater than that in non‐carcinomatous tissues, which suggests that transcripts of abnormal FHIT genes are related to the occurrence and development of carcinomas in the digestive tract.

Site specific dependency of second primary cancer in early stage head and neck squamous cell carcinoma.

A study was conducted to determine the site specificity of second primary cancer (SPC) following early (Stage I and II) squamous cell carcinoma of the head and neck (SCH) and its impact on prognosis. Between 1956 and 1999, 1,639 early stage SCHs in 1,609 patients were treated by radiotherapy at the authors' institution. The risk of additional respiratory and upper digestive tract (RUDT) carcinoma and the treatment outcome were reviewed for each SCH site. Second primary RUDT carcinomas were the second most common cause of death (113 cases) after death from primary SCH carcinomas (350 cases). Among the 1,609 early stage SCH patients, 333 second primary cancers were documented in 258 patients, 235 (71%) of which were RUDT carcinomas. The risk of SPCs was 3.2% per year, and the risk of SPCs in the RUDT region was 2.3% per year. The risk of SPCs was almost two times higher in males (3.7% per year) than in females (2.2% per year). The highest risk of SPC was observed in the oro-hypopharynx index cancer group (8.5% per year), and the lowest risks were observed in the epipharynx group (0% per year) and the maxillary sinus group (1.4% per year). Different SPC risks according to the SCH site result in a different prognosis for each site of early stage SCH. Long-term follow-up care after the initial treatment for early SCH should be continued according to the site of the initial SCH.

The overexpression of elongation factor 1 gamma mRNA in gastric carcinoma

Elongation factor 1 gamma (EF1 gamma) has been isolated from a pancreatic cancer cell line, while the overexpression of EF1 gamma has also been observed in colorectal carcinomas and adenomas. There is, however, still little information on the expression of EF1 gamma in gastric carcinoma. The authors examined the expression of EF1 gamma mRNA in 30 gastric carcinomas and their corresponding paired adjacent normal mucosae obtained during surgery while also examining 10 human digestive tract carcinoma cell lines using Northern blot hybridization. An overexpression was observed in 22 (73%) of 30 gastric carcinomas, relative to the corresponding normal tissue. In a clinicopathologic study, no relationship was observed between the overexpression of EF1 gamma mRNA and the histologic grading or depth of tumor invasion. However, 15 (68%) of 22 overexpressed cases were positive for vascular permeation, whereas only 1 of 8 nonoverexpressed cases was positive for vascular permeation, and the difference was significant (P < 0.05). Nine (90%) of 10 with more than a 10-fold overexpression relative to the corresponding normal tissue showed severe vascular permeation in the histologic specimens. Conversely, the expression of EF1 gamma was observed not only in the pancreatic and gastric carcinoma cell lines, but also in the hepatic, ileocecal, duodenal, and colon carcinoma cell lines. The overexpression of EF1 gamma mRNA was observed in both the gastric carcinoma tissue and in all the other cell lines examined. This probable correlation with vascular permeation in gastric carcinoma is thus considered to provide another piece of useful pathologic information.

Cytokines and pancreatic cancer the effect of rIFN-γ, HuLelFN, rTNF-α, and LAK-cells on pancreatic and other gastrointestinal tumors in vitro

A panel of 10 digestive tract carcinoma cell lines (6 pancreatic carcinomas) was assayed for their sensitivity to HuLeIFN, human rIFN-gamma, rTNF-alpha and allogeneic human LAK-cells in vitro. In addition, a combination of rIFN-gamma + rTNF-alpha was tested on 3 pancreatic carcinoma cell lines. Whereas 6/7 cell lines were completely resistant to HuLeIFN, rIFN-gamma and rTNF-alpha did inhibit growth of some carcinomas tested. The individual sensitivity was heterogenous as is already known from cytostatics. Response to rIFN-gamma tended to increase with increment of cell doubling time. Only high concentrations (greater than 1000 U/ml) of rIFN-gamma displayed cytotoxicity on sensitive tumors. The antitumoral effect of rIFN-gamma was stimulated by rTNF-alpha. As revealed by isobole analysis this interaction was synergistic in all pancreatic carcinomas tested. In comparison to rIFN-gamma or rTNF-alpha the response to LAK-cells was slightly superior at high effector target ratios, even though heterogenous.